Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences

• Published in: Leukemia Vol. 31; no. 4; pp. 821 - 828
• Main Authors: Waanders, E, Scheijen, B, Jongmans, M C J, Venselaar, H, van Reijmersdal, S V, van Dijk, A H A, Pastorczak, A, Weren, R D A, van der Schoot, C E, van de Vorst, M, Sonneveld, E, Hoogerbrugge, N, van der Velden, V H J, Gruhn, B, Hoogerbrugge, P M, van Dongen, J J M, Geurts van Kessel, A, van Leeuwen, F N, Kuiper, R P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2017; Nature Publishing Group
• Subjects: 45; 45/23; 631/208/68; 631/208/69; 631/208/737; 631/80/86; 692/699/67/1990/283/2125; 692/699/67/2332; 82/1; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Alleles; Amino Acid Substitution; Cancer; Cancer Research; Care and treatment; Children; Codons; Conformation; Critical Care Medicine; Diagnosis; Domains; Enzyme inhibitors; Exome; Female; Gene mutation; Genetic Association Studies; Genetic Predisposition to Disease; Genetics; Genomes; Genotype; Germ-Line Mutation; Hematology; High-Throughput Nucleotide Sequencing; Humans; Intensive; Internal Medicine; Janus kinase; Kinases; Leukemia; Life sciences; Lymphatic leukemia; Male; Medicine; Medicine & Public Health; Models, Molecular; Mutation; Oncology; original-article; Patients; Pediatrics; Phosphorylation; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein-tyrosine kinase; Remission (Medicine); Software; STAT Transcription Factors - metabolism; T cell antigen receptors; TYK2 Kinase - chemistry; TYK2 Kinase - genetics; TYK2 Kinase - metabolism; Tyk2 protein; Tyrosine; United States > US; Netherlands; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.277

The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2 , a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this autoregulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.